Overview

Also Known As:tetO-208 TDP-43 transgenic line #2

TetO-208 TDP-43 transgenic line 2 mice have a Tet-responsive element and mouse prion protein promoter sequences directing expression of a human TDP-43 C-terminal fragment (amino acids 208-414), or 208 TDP-43 CTF, that is associated with frontotemporal lobar degeneration with TDP-43 pathology in human brain. These mice may be used to generate Tet-Off/Tet-On mutant animals with conditional (inducible/reversible) expression of 208 TDP-43 CTF.

Donating Investigator

Virginia M Lee, University of Pennsylvania

Genetic overview

Genetic Background	Generation

Tg(tetO/Prnp-TARDBP*)2Vle

Allele Type
Transgenic (Inducible, Inserted expressed sequence, Humanized sequence)

View Genetics

Research Applications

Neurobiology Research
Research Tools

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

View Price List

Details

Detailed Description

The tetO-208 TDP-43 transgene has the Tet-responsive element (TRE or tetO) and mouse prion protein promoter sequences (PrP or Prnp) directing expression of amino acids 208-414 from human TDP-43 (TARDBP). Accumulation of the TDP-43 C-terminal fragment (208 TDP-43 CTF) is associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) in human brain.
When these tetO-208 TDP-43 transgenic line 2 mice are exposed to tetracycline-controlled transactivator protein (tTA) or reverse tetracycline-controlled transactivator protein (rtTA), 208 TDP-43 CTF expression in the resulting animals can be regulated with tetracycline or its analog doxycycline (dox).

Breeding the B6C3F1 tetO-208 TDP-43 mice to C57BL/6J-congenic mice with forebrain-specific tTA expression (from Stock No. 003010) results in bigenic Camk2a-tTA/tetO-208 TDP-43 animals (CAMK-208 TDP-43 Tg). Following dox withdrawal, those CAMK-208 TDP-43 Tg mice exhibit highly-insoluble TDP-43 CTF accumulation in neuronal cytoplasm and dendrites, without formation of the large cytoplasmic TDP-43 inclusions seen in FTLD-TDP and ALS tissue. Hippocampus showed progressive neurodegeneration and astrogliosis in the dentate gyrus (DG), accompanied by phosphorylated TDP-43 in the CA1 subfield and ubiquitin and mitochondria accumulations in the stratum lacunosum moleculare (SLM) layer. The observed neurodegeneration was without changes in the level, solubility or subcellular distribution of nuclear endogenous full-length TDP-43, and was also independent of TDP-43 phosphorylation. After 13 months of transgene expression (off-dox), resumption of dox-treatment led to rapid clearance of 208 TDP-43 CTF and phosphorylated TDP-43, which ameliorated neuron loss in the DG despite persistence of ubiquitin accumulation in the SLM.

In addition, breeding B6C3F1 tetO-208 TDP-43 to NEFH-tTA line 8 mice (broad tTA expression in brain but only modest levels in DG granular cells; see Stock No. 025397) results in bigenic NEFH-tTA/tetO-208 TDP-43 animals (NEFH-208 TDP-43 Tg). Following dox withdrawal, NEFH-208 TDP-43 Tg exhibit similarities to CAMK-208 TDP-43 Tg - including high levels of insoluble 208 TDP-43 CTF in the cortex and hippocampus, with accumulation of p409/410 TDP-43 predominantly in the CA1 region and ubiquitin in the SLM region of the hippocampus. Uniquely, NEFH-208 TDP-43 Tg show no overt loss of DG neurons up to 19 months (as <5% of DG cells expressed 208 TDP-43 CTF).

The donating investigator reports that hemizygous tetO-208 TDP-43 transgenic mice are viable and fertile with no observed phenotype defects or behavioral abnormalities, and they have not tried to generate homozygous mice to date (September 2016). The transgene insertion site(s) is not known. Multiple copies are likely, however, as the inducible expression level of TDP-43_208-414 in hemizygous mice is 3-6-fold greater than endogenous TDP-43 levels.

Note on tetO/Prp promoter: While the untranslated sequences from Prnp have been shown in other mouse models to result in minimal levels of transgene expression in the brain before Tet-induction (see Stock Nos. 025104/027783), it has not yet been determined if these tetO-208 TDP-43 transgenic line 2 mice exhibit any such expression before Tet-induction (September 2016).

Development

The tetO-208 TDP-43 transgenic line 2 mice were created in the laboratory of Dr. Virginia Man-Yee Lee (University of Pennsylvania).
The tetO-208 TDP-43 transgene has the Tet-responsive element and mouse prion protein non-coding exons 1-2 upstream of a cDNA sequence encoding amino acids 208-414 of human TAR DNA binding protein (TARDBP or TDP-43) followed by the mouse prion protein non-coding exon 3 and 3' UTR of the moPrP.XhoI vector (including polyadenylation signal).

The Tet-responsive element (TRE) contains copies of the 42-bp tet operator sequence (tetO) followed by the constitutively active, minimal human cytomegalovirus promoter (P_minCMV). The tetO-208 TDP-43 transgene used TRE (from pTetSplice bp 1-318) and mouse prion protein (PrP or Prnp) sequences from the moPrP-tetP vector (a modified version of moPrP.XhoI).

The ~6.7 kbp transgene was injected into the pronucleus of fertilized eggs from (C57BL/6J x C3HeJ)F1 matings (B6C3F1/J ; Stock No. 100010). Founder animals were bred to B6C3F1/J for germline transmission. Three founder lines were generated. Founder line 2 had the highest inducible expression of 208 TDP-43 C-terminal fragments (CTFs), and all three lines had the same inducible 208 TDP-43 CTF distribution and biochemical properties.

The tetO-208 TDP-43 transgenic line 2 was then maintained by breeding hemizygous mice with B6C3F1/Crl for several generations, and then hemizygous males (black or agouti) were sent to The Jackson Laboratory Repository in 2016.

Upon arrival, sperm was cryopreserved. To establish our living colony, an aliquot of the frozen sperm was used to fertilize oocytes from B6C3F1/J females (Stock No. 100010). After that, our live colony will be maintained by breeding hemizygous mice with wildtype (noncarrier) mice from the colony, and animals will be selected to have the C57BL/6-derived Pde6b allele (rather than the C3H-derived Pde6b^rd1). Our colony will also be periodically bred to B6C3F1/J mice (Stock No. 100010) to maintain ~50/50% mix of C57BL/6 and C3H.

The donating investigator reports that the transgene insertion site(s) is not known. Multiple copies are likely, however, as the inducible expression level of TDP-43_208-414 in hemizygous mice is 3-6-fold greater than endogenous TDP-43 levels.

Expression Data

Expressed Gene	TARDBP, TAR DNA binding protein, human
Site of Expression	Primarily in the cortex, hippocampus and olfactory bulb of the brain.

Control Suggestions

Noncarrier

Approximate Controls

100010 B6C3F1/J

Additional Information

Considerations for Choosing Controls

Selected References

Walker AK; Tripathy K; Restrepo CR; Ge G; Xu Y; Kwong LK; Trojanowski JQ; Lee VM. 2015. An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice. Hum Mol Genet 24(25):7241-54PubMed: 26476406 MGI: J:226974

View All References

Genetics

Tg(tetO/Prnp-TARDBP*)2Vle

Allele Symbol: Tg(tetO/Prnp-TARDBP*)2Vle

Allele Name	transgene insertion 2, Virginia M Y Lee
Allele Type	Transgenic (Inducible, Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	tetO-208 TDP-43 Tg
Gene Symbol and Name	Tg(tetO/Prnp-TARDBP*)2Vle, transgene insertion 2, Virginia M Y Lee
Gene Synonym(s)
Promoter	tetO, tet operator,
Expressed Gene	TARDBP, TAR DNA binding protein, human
Site of Expression	Primarily in the cortex, hippocampus and olfactory bulb of the brain.
Strain of Origin	(C57BL/6J x C3H/HeJ)F1
Chromosome	UN
Molecular Note	The transgenic construct contains the Tet-responsive element and mouse prion protein non-coding exons 1-2 upstream of a cDNA sequence encoding amino acids 208-414 of human TAR DNA binding protein (TARDBP or TDP-43) followed by the mouse prion protein non-coding exon 3 and 3' UTR of the moPrP.XhoI vector (including polyadenylation signal). Three founder lines were generated. Founder line 2 had the highest inducible expression of 208 TDP-43 C-terminal fragments (CTFs), and all three lines have the same inducible 208 TDP-43 CTF distribution and biochemical properties.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Neurobiology Research
- Myelination Defects
  - peripheral neuropathy
- Amyotrophic Lateral Sclerosis (ALS)
- Neurodegeneration
- Neuromuscular defects
- Ataxia (Movement) Defects
- Tet Expression System
  - tTA/rtTA Responsive Strains
Research Tools
- Neurobiology Research
  - Tetop Tet System
- Tet Expression Systems
  - tTA/rtTA Responsive Strains
- Genetics Research
  - Mutagenesis and Transgenesis: Tetop Tet System

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Tg(Camk2a-tTA)1Mmay/0 Tg(tetO/Prnp-TARDBP)2Vle/0
involves: C3H/HeJ C57BL/6J

nervous system phenotype

astrocytosis
- increase in GFAP reactivity 10 months after Dox removal

hippocampal neuron degeneration

loss of hippocampal neurons
- loss is progressive resulting in an 80% decrease in neurons at 19 months
- number of dentate gyrus neurons is decreased in mice at 10, 16 and 19, but not at 5, months after Dox removal as compared to controls
- reintroduction of Dox clears Tardbp C-terminal fragments (CTF) from the brain and halts neuron loss

neuronal cytoplasmic inclusions
- accumulation of ubiquitin and mitochondrial proteins in distal dendrites of the stratum lacunosum moleculare (SLM) layer of the hippocampus 5 months after Dox withdrawal, reintroduction of Dox does not clear ubiquitin
- ubiquitin forms a discrete punctate pattern in SLM

Genotype: Tg(NEFH-tTA)8Vle/0 Tg(tetO/Prnp-TARDBP)2Vle/0
involves: C3H/HeJ C57BL/6J

mammalian phenotype

nervous system phenotype
- Normal - loss of neurons is not observed in the dentate gyrus after Dox withdrawal

nervous system phenotype

neuronal cytoplasmic inclusions
- accumulation of ubiquitin in distal dendrites of the stratum lacunosum moleculare (SLM) layer of the hippocampus after Dox withdrawal

References

Walker AK; Tripathy K; Restrepo CR; Ge G; Xu Y; Kwong LK; Trojanowski JQ; Lee VM. 2015. An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice. Hum Mol Genet 24(25):7241-54PubMed: 26476406 MGI: J:226974

Additional - Tg(tetO/Prnp-TARDBP*)2Vle related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tg(tetO/Prnp-TARDBP*)2Vle
- Probe:Pde6b Probe
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining our live colony, hemizygous mice are bred to wildtype (noncarrier) mice from the colony, and animals are selected to have the C57BL/6-derived Pde6b allele (rather than the C3H-derived Pde6b^rd1). The colony will be periodically bred to B6C3F1/J mice (Stock No. 100010) to maintain ~50/50% mix of C57BL/6 and C3H, after which we will continue to select animals with the C57BL/6-derived Pde6b allele.
The donating investigator reports that hemizygous tetO-208 TDP-43 transgenic mice are viable and fertile with no observed phenotype defects or behavioral abnormalities. To date (September 2016), it has not been attempted to make this strain homozygous.
- Additional Breeding and Husbandry Support
Mating System
- Hemizygote x B6C3F1/J (JR. 100010) and reci
Citation
When using the tetO-208 TDP-43 transgenic line #2 mouse strain in a publication, please cite the originating article(s) and include JAX stock #028590 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Hemizygous or non carrier for Tg(tetO/Prnp-TARDBP*)2Vle

Related Products and Services

Frozen Mouse Embryo	B6C3-Tg(tetO/Prnp-TARDBP*)2Vle/J	$2595.00
Frozen Mouse Embryo	B6C3-Tg(tetO/Prnp-TARDBP*)2Vle/J	$2595.00
Frozen Mouse Embryo	B6C3-Tg(tetO/Prnp-TARDBP*)2Vle/J	$3373.50
Frozen Mouse Embryo	B6C3-Tg(tetO/Prnp-TARDBP*)2Vle/J	$3373.50

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

JAX® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCT(S)" means biological materials supplied by JACKSON, and their derivatives. "SERVICES" means projects conducted by JACKSON for other parties that may include but are not limited to the use of MICE or PRODUCTS. "RECIPIENT" means each recipient of MICE, PRODUCTS, or SERVICES provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE, PRODUCTS or SERVICES from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON’s prior written authorization.

No Warranty

MICE, PRODUCTS AND SERVICES ARE PROVIDED "AS IS". JACKSON EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS, IMPLIED, OR STATUTORY, WITH RESPECT TO MICE, PRODUCTS OR SERVICES, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY WARRANTY OF NON-INFRINGEMENT OF ANY PATENT, TRADEMARK, OR OTHER INTELLECTUAL PROPERTY RIGHTS.

Credit for PRODUCTS or SERVICES

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of, PRODUCTS or SERVICES, JACKSON will, at its option, provide credit or replacement for the PRODUCT received or the SERVICES provided; JACKSON makes no other representations and this shall be the exclusive remedy of the purchaser. Please note specific policy for live mice.

Animal Care and Use for SERVICES

Consistent with the requirement for a written understanding regarding animal care and use, the JACKSON Animal Care and Use Committee will review the animal care and use protocol(s) associated with any SERVICES to be performed at JACKSON, and JACKSON shall have ultimate responsibility and authority for the care of animals while on site or in JACKSON custody.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS, or SERVICES, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS, or SERVICES from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE, PRODUCTS or SERVICES are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or SERVICES. In addition, special terms and conditions of sale of certain MICE, PRODUCTS, or SERVICES may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and SERVICES by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or SERVICES shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or SERVICES by JACKSON.

Also Known As:tetO-208 TDP-43 transgenic line #2

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Tg(tetO/Prnp-TARDBP*)2Vle

Allele Symbol: Tg(tetO/Prnp-TARDBP*)2Vle

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Tg(Camk2a-tTA)1Mmay/0 Tg(tetO/Prnp-TARDBP*)2Vle/0involves: C3H/HeJ * C57BL/6J

nervous system phenotype

Genotype: Tg(NEFH-tTA)8Vle/0 Tg(tetO/Prnp-TARDBP*)2Vle/0involves: C3H/HeJ * C57BL/6J

mammalian phenotype

nervous system phenotype

References

Additional - Tg(tetO/Prnp-TARDBP*)2Vle related

Genotyping Protocols

Breeding Considerations

Mating System

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Genotype: Tg(Camk2a-tTA)1Mmay/0 Tg(tetO/Prnp-TARDBP)2Vle/0
involves: C3H/HeJ C57BL/6J

Genotype: Tg(NEFH-tTA)8Vle/0 Tg(tetO/Prnp-TARDBP)2Vle/0
involves: C3H/HeJ C57BL/6J